Selective removal of cancer cells plays a key role in treatment of cancer. Various types of genetic mutations occur in cells during the processes of oncogenesis and cancer progression (Vogelstein, B. et al., Trends Genet 9, 138-41, 1993), and such mutations can be the targets of cancer gene therapy. When genes of a given type are overexpressed, such genes exhibit the effects of selectively killing cancer cells. Representative examples of such genes include p53 (Chen, P. L. et al., Science 250, 1576-80, 1990; Fujiwara, T. et al., J. Natl. Cancer Inst., 86, 1458-62, 1994; Nielsen, L. L. et al., Cancer Gene Ther., 4, 129-38, 1997) and mda-7 (Fisher, P. B. et al., Cancer Biol. Ther., 2, S23-37, 2003), and such genes are known as cancer suppressor genes.
Meanwhile, the REIC/Dkk-3 gene is known to be associated with cell immortalization, and suppression of expression of such genes in cancer cells has been reported (WO 01/038523, Tsuji, T. et al., Biochem. Biophys. Res. Commun., 268, 20-4, 2000; Tsuji, T. et al., Biochem. Biophys. Res. Commun., 289, 257-63, 2001; Nozaki, I. et al., Int. J. Oncol., 19, 117-21, 2001; and Kurose, K. et al., J. Urol., 171, 1314-8, 2004).
The REIC/Dkk-3 gene is a member of the Dkk family, and it is suggested that such gene inhibits Wnt signal transmission via a Wnt receptor (Bafico, A. et al., Nat. Cell Biol., 3, 683-6, 2001 and Hoang, B. H. et al., Cancer Res., 64, 2734-9, 2004). It is reported that the Wnt gene plays multiple roles in important biological conditions, such as cell growth, differentiation, and canceration (Moon, R. T. et al., Science 296, 1644-6, 2002). Accordingly, the Dkk family (the presence of 4 genes is known in humans at present) is also considered to play a key role in cell growth, differentiation, and canceration, although most of its functions remain unknown.
At present, research regarding endoplasmic reticulum stress has been in progress. Secretory proteins synthesized in vivo is transferred to the endoplasmic reticulum and efficiently folded by a variety of molecular chaperones or folding enzymes. However, folding cannot always be sufficiently performed, abnormal proteins of a higher-order structure are accumulated in the endoplasmic reticulum in such a case, and endoplasmic reticulum stress is induced thereby (D. Thomas Rutkowski et al., TRENDS in Cell Biology Vol. 14, No.1, p. 20-28, January 2004). It is reported that cells may die because of apoptosis induced by the endoplasmic reticulum stress (Mori K., Traffic, 4, 519-528, 2003).